B-BOP Exploration of the dynamics of Blood-Brain barrier regulation for optimized management of chemical exposure to OrganoPhosphate

B-BOP
Exploration of the dynamics of Blood-Brain barrier regulation for optimized management of chemical exposure to OrganoPhosphate

ANR ASTRID 2022

Project coordinator:
Dr. Nicolas Tournier, Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), Service Hospitalier Frédéric Joliot, Orsay, France.

Project Partner:
• Pr. Cyrille Orset, INSERM U1237, Blood and Brain Caen Normandie Institute, Caen, France.
• Dr. Gregory Dal Bo, Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France
• Dr. Candice Chapouly, Université de Bordeaux, Institut national de la santé et de la recherche médicale (INSERM), Biology of Cardiovascular Diseases, Pessac, France.

Organophosphorus compounds (OP), initially developed as plant protection products, are used for military purposes as nerve agents (NA) (Sarin, VX or Novitchok). They pose a threat to military and civilian populations. They cause irreversible inhibition of peripheral and central cholinesterases, blocking the breakdown of acetylcholine. The majority of neuroprotective research focuses on seizures induced by high doses of OP. The effects of lower, less symptomatic or even asymptomatic doses are little studied. However, very long-term persistent mood disorders are observed after a single exposure to an asymptomatic dose of OP in animals. Cognitive and neuropathic deficits have been observed in victims exposed to low doses. There is a crucial need for exposure biomarkers that allow i) early pre-symptomatic diagnosis and ii) evaluation and/or treatment of organophosphate and related compounds intoxications in the long term.
To date, the neurotoxicity of OPs has been mainly addressed through the lens of neuronal and synaptic perturbations. The blood-brain barrier (BBB) represents the main exchange surface between the circulation and the brain tissue. Damage to the BBB and its role in neurotoxicity following OP intoxication remains poorly understood and constitutes an original diagnostic target and potential therapeutic strategy. The B-BOP project aims to study the integrity, transport and activation properties of the BBB following OP exposure and to evaluate them as a biomarker for the detection and prediction of brain damage. This will allow the evaluation of novel therapeutic strategies aimed at taking advantage of BBB damage, either by allowing the cerebral passage of antidote or by restoring the physiological properties of the BBB.
We have chosen to focus on in vivo imaging methods in order to i) perform longitudinal studies and limit the number of animals needed for the project, ii) allow a 3-dimensional mapping of the effect of OPs in all brain regions, and iii) to inscribe this project in a translational approach with clinical diagnostic and/or theranostic perspectives in exposed patients. Moreover, the data obtained by in vivo imaging in animals will be confronted with histological data obtained post-mortem to allow a molecular interpretation.
The comparison of the response intensity of the different biomarkers and their temporal course will allow to evaluate the hypothesis that there is a synchronicity between the regulation of the BBB and the neurological and behavioral consequences of intoxication. This will allow to evaluate the contribution of BBB perturbations to the neurotoxic mechanisms of action of OPs. The relative contribution of each biomarker will allow to establish their relevance for the detection, monitoring or prediction of the neurotoxic consequences of OPs in the long term. The longitudinal approach will also allow to define an optimal temporal window to estimate the degree of BBB damage from non-invasive imaging data in order to optimize therapeutic strategies.
The work program is based on the synergy and expertise of 4 groups recognized in 1/ imaging of the integrity and transport properties of the BBB (CEA/SHFJ), 2/ imaging of the integrity and inflammatory activation of BBB endothelial cells (INSERM U1237-PhIND), 3/ the study of molecular interactions between BBB endothelial cells and glial cells (INSERM U1034) and 4/ the neurophysiological and behavioral study of OP intoxication and the validation of a mouse model of exposure to OP (IRBA).